title: Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons.
abstract: Rett syndrome (RTT) is caused by mutations of MECP2, a methyl CpG binding protein thought to act as a global transcriptional repressor. Here we show, using an isogenic human embryonic stem cell model of RTT, that MECP2 mutant neurons display key molecular and cellular features of this disorder. Unbiased global gene expression analyses demonstrate that MECP2 functions as a global activator in neurons but not in neural precursors. Decreased transcription in neurons was coupled with a significant reduction in nascent protein synthesis and lack of MECP2 was manifested as a severe defect in the activity of the AKT/mTOR pathway. Lack of MECP2 also leads to impaired mitochondrial function in mutant neurons. Activation of AKT/mTOR signaling by exogenous growth factors or by depletion of PTEN boosted protein synthesis and ameliorated disease phenotypes in mutant neurons. Our findings indicate a vital function for MECP2 in maintaining active gene transcription in human neuronal cells.
authors.affiliation: The Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Haoyi
authors.initials: H
authors.lastname: Wang
authors.forename: Julien
authors.initials: J
authors.lastname: Muffat
authors.forename: Albert W
authors.initials: AW
authors.lastname: Cheng
authors.forename: David A
authors.initials: DA
authors.lastname: Orlando
authors.forename: Jakob
authors.initials: J
authors.lastname: Lovén
authors.forename: Show-Ming
authors.initials: SM
authors.lastname: Kwok
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Feldman
authors.forename: Helen S
authors.initials: HS
authors.lastname: Bateup
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.forename: Dirk
authors.initials: D
authors.lastname: Hockemeyer
authors.forename: Maisam
authors.initials: M
authors.lastname: Mitalipova
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lewis
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: Mriganka
authors.initials: M
authors.lastname: Sur
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
mesh_terms: D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D014176:Protein Biosynthesis / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics* / Q000473:pathology*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2